The invention relates to imaging agents and methods for SPECT, and more particularly to imaging agents radiolabeled with 99mTc.
The most widely used radionuclide in nuclear medicine is technetium-99m (99mTC; T1/2=6.0 h, 140 KeV γ emission). While the majority of clinically approved 99Tc-radiopharmaceuticals are perfusion-type agents (diagnostic images of blood flow), there is a growing interest to develop and commercialize single photon emission computed tomography (SPECT) imaging agents that target specific biomarkers.
Exploitation of this opportunity requires the creation of ligand which acts as a technetium chelator to incorporate 99mTc and is capable of regioselectively conjugating to a variety of vectors, including biomolecules. Vectors refer to a vehicle used to transfer material to a target or target site. Ideally, the ligand should be capable of incorporating 99mTc without impairing the biological properties of the vector.
While ligands capable of chelating with 99mTc are well known, few ligands meet the criteria needed to develop an effective agent. For example in certain synthetic methodologies 99mTc incorporation is achieved under basic conditions, which can be deleterious to certain peptides/proteins.
For example European Patent EP0738158 and U.S. Pat. No. 7,597,875 disclose a ligand with an all-carbon bridge and shown in FIG. 1 (structure A). The ligand (A) is capable of conjugation a broad array of vectors via the primary nitrogen. However, like diaminodioximes in general it requires a pH of approximately 9-10 to label optimally. This pH is incompatible with many sensitive biomolecules. Furthermore the synthesis of the structure A yields mono, bi, and tri functionalized products from which the desired bi-functionalized chelate must be isolated by preparative HPLC.
U.S. Pat. No. 7,049,289 discloses a ligand, (FIG. 1, structure B), that may also be appropriate for conjugation a broad array of vectors via the primary nitrogen; it is also synthetically more accessible than the all carbon backbone (structure A). However as taught in U.S. Pat. No. 7,597,875, this ligand does not form a single radiolabeled species with 99mTc under mild conditions.
Similarly, U.S. Pat. No. 5,688,487 and U.S. Pat. No. 5,997,843 disclose a ligand, (FIG. 1, structure C) with an all carbon bridge and nitroimidazole vector (X) attached at the C1 position. This construct is limited in that it is not easy for a facile and broad conjugation to vectors as the vector is incorporated early in a multistep synthesis.
As such, the development of an alternative approach involving chelation that is effective at slightly basic to acidic pH and is readily synthesized would provide a technology to enable technetium radiolabeling of vectors without pH limitations. Furthermore it would be desirable to have 99mTc incorporation in a single step in a manner suitable for clinical production of agents with high effective specific activity. Accordingly, there is a need for imaging systems and methods that can provide a high resolution, high sensitivity image in a shorter period of time and which may be produced under mild aqueous conditions.